Burbrink (2001) used cytochrome b sequences to examine phylogenetic relationships among Elaphe guttata populations (one specimen from each of 53 locations throughout most of the range). He found no support for recognition of the nominal subspecies intermontanus and meahllmorum as distinct taxa; these appear to be junior synonyms of E. guttata emoryi. Burbrink identified three partitions within E. guttata: an eastern partition (east of the Mississippi River) corresponding to E. guttata guttata, a western partition corresponding to E. guttata emoryi (including E. g. intermontanus and E. g. meahllmorum), and a central partition in western Louisiana and eastern Texas. The central partition, in pine and pine-hardwood habitat west of the Mississippi River, clustered closer to the eastern partition than to the western partition. Burbrink recognized the three partitions as species using evolutionary species criteria: (1) Elaphe guttata (Red Corn Snake) (eastern partition , (2) Elaphe emoryi (Great Plains Rat Snake) (western partition), and (3) Elaphe slowinskii (Slowinski's Corn Snake) (central partition). One specimen (Hidalgo County, Texas) of the central partition (based on cytochrome b characteristics) was located outside the presumed geographic area and habitat identified for other members of that partition. Crother et al. (2003) adopted these changes. Ernst and Ernst (2003) recognized E. emoryi and E. guttata as distinct species, but their manuscript evidently was completed before Burbrink's paper was published; they did not comment on E. slowinskii.

Utiger et al. (2002) examined mtDNA variation in New World and Old World "Elaphe" and determined that North American rat snakes included in the genus Elaphe form a monophyletic lineage that is distinct from Old World snakes that also have been regarded as Elaphe. They resurrected the genus Pantherophis for the rat snakes north of Mexico, including the following species: Pantherophis obsoletus (and P. alleghaniensis and P. spiloides, if one recognizes those taxa as species), P. guttatus, P. emoryi, P. vulpinus, P. gloydi, and P. bairdi. Crother et al. (2003) noted this proposal but did not adopt it, pending further review. Burbrink and Lawson (2007) agreed with Utiger et al. (2002) that these species do not belong in Elaphe, but suggested that the genus Pantherophis might belong in Pituophis. We retain this species in Pantherophis, following Utiger et al. (2002) pending further information on the relationships of these taxa.

This species is endemic to the eastern and southeastern United States. Its range extends from southern New Jersey, Maryland, and Kentucky southward to southeastern Louisiana, southern Mississippi, southern Alabama, and southern Florida (Conant and Collins 1991, Burbrink 2002). Introduced populations have been recorded on several islands of the Caribbean, with established introduced populations in the Bahamas (New Providence and Grand Bahama), Grand Cayman, the US Virgin Islands (St. Thomas), and the Lesser Antilles (Saint Barthélemy; and Guana Cay of Pelikan, a satellite of Sint Maarten) (Buckner and Franz 1994, Henderson and Powell 2009, Perry et al. 2003, Powell and Henderson 2012, Seidel and Franz 1994, R. Powell pers. comm. 2016). It is unknown whether all of these introduced populations are extant (R. Powell pers. comm. 2016), although it is still (uncommonly) recorded on Grand Cayman. Isolated records, presumed to be waifs rather than established populations, are known from multiple additional islands within most of these island groups and from Grand Turk in Turks and Caicos (R. Powell pers. comm. 2016).

This species is represented by a large number of occurrences (subpopulations). Adult population size is unknown but presumably exceeds 10,000 and probably exceeds 100,000. Extent of occurrence, area of occupancy, number of subpopulations, and population size probably are relatively stable or declining at a rate of less than 10% over 10 years or three generations.